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Here, we describe a pyridyl-pyrazole-piperidine scaffold and the lead compound 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (\n                  <jats:bold>32<\/jats:bold>\n                  ), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Structure-activity relationship studies, guided by biochemical and cellular assays using multiple human and murine protein constructs and cells, identified SHIP1-active ligands. A thermal shift assay using full-length SHIP1 was used to assess compounds for cellular target engagement, while studies in IL-4 conditioned THP-1 cells was used to demonstrate changes in downstream AKT signaling. Targeted lipidomics revealed changes in the overall phosphoinositide pool consistent with SHIP1 target engagement and reduction of phospho-AKT levels. In a protein-lipid overlay assay, compound\n                  <jats:bold>32<\/jats:bold>\n                  induced changes in the relative association of SHIP1 with multiple phosphatidylinositols on a membrane surface. In high-content cellular imaging assays, compound\n                  <jats:bold>32<\/jats:bold>\n                  enhanced the uptake of myelin\/membrane debris and fibrillar amyloid by primary murine microglia, phenocopying a genetic model with reduced SHIP1 expression. Finally, oral administration of compound\n                  <jats:bold>32<\/jats:bold>\n                  resulted in brain exposure sufficient to alter gene expression and reduce IL-1\u03b2 levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer\u2019s disease. Collectively, these results define a scaffold with SHIP1 target engagement, CNS exposure, and\n                  <jats:italic>in vivo<\/jats:italic>\n                  activity, providing a foundation for the optimization of brain-penetrant SHIP1 ligands suitable for further mechanistic studies and therapeutic development for the treatment of Alzheimer\u2019s disease.\n                <\/jats:p>","DOI":"10.64898\/2025.12.31.697127","type":"posted-content","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T23:20:12Z","timestamp":1767396012000},"source":"Crossref","is-referenced-by-count":0,"title":["Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer\u2019s Disease Models"],"prefix":"10.64898","author":[{"given":"Cynthia D.","family":"Jesudason","sequence":"first","affiliation":[{"name":"Lgenia, Fortville, Indiana 46040, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Rangel-Barajas","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana 46202, United States"},{"name":"Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin J.","family":"Beach","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana 46202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel E.","family":"Beck","sequence":"additional","affiliation":[{"name":"Purdue University, West Lafayette, Indiana 47907, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac H.","family":"Caballero-Floran","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine, Indianapolis, Indiana 46202, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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